KR100546495B1 - Benzonitrile Synthesis Method - Google Patents
Benzonitrile Synthesis Method Download PDFInfo
- Publication number
- KR100546495B1 KR100546495B1 KR1019970048513A KR19970048513A KR100546495B1 KR 100546495 B1 KR100546495 B1 KR 100546495B1 KR 1019970048513 A KR1019970048513 A KR 1019970048513A KR 19970048513 A KR19970048513 A KR 19970048513A KR 100546495 B1 KR100546495 B1 KR 100546495B1
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- aryl
- heteroaryl
- compound
- formula
- Prior art date
Links
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 title description 12
- 238000001308 synthesis method Methods 0.000 title 1
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 239000003513 alkali Substances 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- -1 alkali metal cyanide Chemical class 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 12
- 150000004703 alkoxides Chemical class 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052802 copper Inorganic materials 0.000 claims description 10
- 239000010949 copper Substances 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052759 nickel Inorganic materials 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 6
- 239000011701 zinc Substances 0.000 claims description 6
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 claims description 5
- QEKXARSPUFVXIX-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dibromide Chemical compound [Ni+2].[Br-].[Br-].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QEKXARSPUFVXIX-UHFFFAOYSA-L 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 3
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims description 3
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 3
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000005751 Copper oxide Substances 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- 229910000431 copper oxide Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- QCYXGORGJYUYMT-UHFFFAOYSA-N nickel;triphenylphosphane Chemical compound [Ni].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QCYXGORGJYUYMT-UHFFFAOYSA-N 0.000 claims description 2
- VGZIOHINNQGTOU-UHFFFAOYSA-N nickel;triphenylphosphane Chemical compound [Ni].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VGZIOHINNQGTOU-UHFFFAOYSA-N 0.000 claims description 2
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical group [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000007513 acids Chemical class 0.000 abstract description 2
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical class OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 abstract 1
- 150000005171 halobenzenes Chemical class 0.000 abstract 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 24
- 238000004817 gas chromatography Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- JPKBIODDVOUHAD-UHFFFAOYSA-N 3-methoxy-2-methylbenzonitrile Chemical compound COC1=CC=CC(C#N)=C1C JPKBIODDVOUHAD-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000007333 cyanation reaction Methods 0.000 description 8
- LTVRGAWOEOKGJZ-UHFFFAOYSA-N 1-chloro-3-methoxy-2-methylbenzene Chemical compound COC1=CC=CC(Cl)=C1C LTVRGAWOEOKGJZ-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- JPCISVSOTKMFPG-UHFFFAOYSA-N 3-methoxy-2-methylbenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1C JPCISVSOTKMFPG-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000006198 methoxylation reaction Methods 0.000 description 5
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 0 *c1cccc(C#N)c1* Chemical compound *c1cccc(C#N)c1* 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001491 aromatic compounds Chemical group 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 2
- DMEDNTFWIHCBRK-UHFFFAOYSA-N 1,3-dichloro-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1Cl DMEDNTFWIHCBRK-UHFFFAOYSA-N 0.000 description 2
- RYMMNSVHOKXTNN-UHFFFAOYSA-N 1,3-dichloro-5-methyl-benzene Natural products CC1=CC(Cl)=CC(Cl)=C1 RYMMNSVHOKXTNN-UHFFFAOYSA-N 0.000 description 2
- FPEUDBGJAVKAEE-UHFFFAOYSA-N 1,3-dimethoxy-2-methylbenzene Chemical compound COC1=CC=CC(OC)=C1C FPEUDBGJAVKAEE-UHFFFAOYSA-N 0.000 description 2
- RIERSGULWXEJKL-UHFFFAOYSA-N 3-hydroxy-2-methylbenzoic acid Chemical compound CC1=C(O)C=CC=C1C(O)=O RIERSGULWXEJKL-UHFFFAOYSA-N 0.000 description 2
- BQAMEYNBQIHQPO-UHFFFAOYSA-N 3-hydroxy-2-methylbenzonitrile Chemical compound CC1=C(O)C=CC=C1C#N BQAMEYNBQIHQPO-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- MGAXYKDBRBNWKT-UHFFFAOYSA-N (5-oxooxolan-2-yl)methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC(=O)CC1 MGAXYKDBRBNWKT-UHFFFAOYSA-N 0.000 description 1
- XQUOYBYNFNGFCJ-UHFFFAOYSA-N 1-methoxy-3-(3-methoxy-2-methylphenyl)-2-methylbenzene Chemical group COC1=CC=CC(C=2C(=C(OC)C=CC=2)C)=C1C XQUOYBYNFNGFCJ-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- DTFKRVXLBCAIOZ-UHFFFAOYSA-N 2-methylanisole Chemical compound COC1=CC=CC=C1C DTFKRVXLBCAIOZ-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZRXHLJNBNWVNIM-UHFFFAOYSA-N 3-methyl-1-benzofuran Chemical compound C1=CC=C2C(C)=COC2=C1 ZRXHLJNBNWVNIM-UHFFFAOYSA-N 0.000 description 1
- ZBJJDYGJCNTNTH-UHFFFAOYSA-N Betahistine mesilate Chemical group CS(O)(=O)=O.CS(O)(=O)=O.CNCCC1=CC=CC=N1 ZBJJDYGJCNTNTH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XAVQZBGEXVFCJI-UHFFFAOYSA-M lithium;phenoxide Chemical compound [Li+].[O-]C1=CC=CC=C1 XAVQZBGEXVFCJI-UHFFFAOYSA-M 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- ZGJADVGJIVEEGF-UHFFFAOYSA-M potassium;phenoxide Chemical compound [K+].[O-]C1=CC=CC=C1 ZGJADVGJIVEEGF-UHFFFAOYSA-M 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 125000004436 sodium atom Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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- C07—ORGANIC CHEMISTRY
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
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Abstract
할로벤젠에서의 친핵성 치환 반응이 촉매 존재하에 수행된다. 보다 상세하게는, 본 발명은 치환된 2,6-디할로벤젠으로부터, 선택적으로 치환된 하이드록시벤조산과 알콕시벤조산 및 선택적으로 치환된 하이드록시벤조니트릴과 알콕시벤조니트릴을 제조하는 방법을 제공하는 것이다.The nucleophilic substitution reaction in halobenzene is carried out in the presence of a catalyst. More specifically, the present invention provides a process for preparing optionally substituted hydroxybenzoic and alkoxybenzoic acids and optionally substituted hydroxybenzonitrile and alkoxybenzonitriles from substituted 2,6-dihalobenzenes. .
Description
본 발명은 방향족 환에 알콕시 또는 하이드록시 치환기를 갖는 방향족 카복실산과 니트릴을 제조하는 방법에 관한 것이다. The present invention relates to a process for producing aromatic carboxylic acids and nitriles having alkoxy or hydroxy substituents on aromatic rings.
특히, 방향족 환에 알콕시 또는 하이드록시 치환기를 갖는 벤조산 또는 벤조니트릴은 농약과 의약품의 제조를 포함하여 여러 가지 상업분야에 사용된다. 다양한 경로들, 예를 들어 US 제5,530,028호에 기술된 바와 같이 디아조 반응을 이용하여 아미노 치환된 벤조산이나 에스테르를 알콕시 또는 하이드록시 치환된 벤조산이나 에스테르로 전환하는 것, 또는 AU-A-12496/83에 기술된 바와 같이 그리냐드 반응 조건을 이용하여 6-클로로-2-메톡시톨루엔을 3-메톡시-2-메틸벤조산으로 전환하는 것 등이 알려져 있음에도 불구하고, 이러한 종류의 산과 니트릴을 보다 저 비용과 고 순도로 제공하는 것이 계속적으로 필요시된다. In particular, benzoic acid or benzonitrile having alkoxy or hydroxy substituents on aromatic rings are used in various commercial fields, including the manufacture of pesticides and pharmaceuticals. Converting amino substituted benzoic acids or esters to alkoxy or hydroxy substituted benzoic acids or esters using various routes, for example, diazo reactions as described in US Pat. No. 5,530,028, or AU-A-12496 / Although it is known to convert 6-chloro-2-methoxytoluene to 3-methoxy-2-methylbenzoic acid using Grignard reaction conditions as described in 83, more Providing low cost and high purity is constantly needed.
본 발명의 목적은 목적하는 벤조산과 벤조니트릴을 제조하기 위한 몇 가지 유리한 방법을 제공하는 것이다. It is an object of the present invention to provide some advantageous methods for producing the desired benzoic acid and benzonitrile.
본 발명은 The present invention
(i) 화학식 I의 화합물을 알칼리 알콕사이드, 알칼리 아록사이드, 알칼리 아릴알콕사이드 또는 알칼리 헤테로아릴알콕사이드와, 임의로는 구리를 포함하는 촉매의 존재하에 반응시켜 화학식 Ⅱa의 화합물을 생성하는 단계 및(i) reacting a compound of formula (I) with an alkali alkoxide, alkali alkoxide, alkali arylalkoxide or alkali heteroarylalkoxide in the presence of a catalyst comprising optionally copper to produce a compound of formula (IIa); and
(ii) 화학식 IIa의 화합물을 알칼리 금속 시아나이드, 아세톤 시아노하이드린 또는 시안화 제1구리와, 니켈을 포함하는 촉매 존재화에 반응시켜 화학식 III의 방향족 시아노 화합물을 형성하는 단계를 포함하는, 화학식 III의 화합물의 제조 방법을 제공한다.(ii) reacting a compound of formula (IIa) with an alkali metal cyanide, acetone cyanohydrin or cuprous cyanide, to a catalyst presence comprising nickel to form an aromatic cyano compound of formula (III) Provided are methods of preparing the compounds of III.
상기식에서, In the above formula,
X는 각각 독립적으로 염소, 브롬, 또는 요오드이며,Each X is independently chlorine, bromine, or iodine,
R은 수소 원자, (C1-C6)알킬, 아릴, 아릴(C1-C2)알킬, 헤테로아릴 또는 헤테로아릴(C1-C2)알킬; 또는 (C1-C3)알킬 및 (C1-C3)알콕시로부터 독립적으로 선택된 1 내지 3개의 치환기로 치횐된 (C1-C6)알킬, 아릴, 아릴(C1-C2)알킬, 헤테로아릴 또는 헤테로아릴(C1-C2)알킬이고,R is a hydrogen atom, (C 1 -C 6 ) alkyl, aryl, aryl (C 1 -C 2 ) alkyl, heteroaryl or heteroaryl (C 1 -C 2 ) alkyl; Or (C 1 -C 3) alkyl and (C 1 -C 3) the chihoen alkoxy with 1 to 3 substituents independently selected from (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 2) alkyl, , Heteroaryl or heteroaryl (C 1 -C 2 ) alkyl,
R1은 CHR2R3, 아릴, 아릴(C1-C2)알킬 또는 헤테로아릴(C1-C2)알킬; 또는 (C1-C3)알킬 및 (C1-C3)알콕시로부터 독립적으로 선택된 1 내지 3개의 치환기로 치횐된 아릴, 아릴(C1-C2)알킬 또는 헤테로아릴(C1-C2)알킬이고,R 1 is CHR 2 R 3 , aryl, aryl (C 1 -C 2 ) alkyl or heteroaryl (C 1 -C 2 ) alkyl; Or (C 1 -C 3) alkyl and (C 1 -C 3) an independently with one to three substituents selected from alkoxy chihoen aryl, aryl (C 1 -C 2) alkyl or heteroaryl (C 1 -C 2 Alkyl,
R2와 R3은 각각 독립적으로 수소 원자 또는 (C1-C5)알킬이거나 (C1-C2)알콕시로 치환된 (C1-C3)알킬이다.R 2 and R 3 are each independently a hydrogen atom or (C 1 -C 5) alkyl or (C 1 -C 2) alkoxy (C 1 -C 3) alkyl substituted with.
또한, 본 발명은 In addition, the present invention
(i) 화학식 I의 화합물을 알칼리 금속 시아나이드, 아세톤 시아노하이드린 또는 시안화 제1구리와, 니켈을 포함하는 촉매 존재하에 반응시켜 화학식 Ⅱb의 방향족 시아노 화합물을 형성하는 단계 및(i) reacting a compound of formula (I) with an alkali metal cyanide, acetone cyanohydrin or cuprous cyanide in the presence of a catalyst comprising nickel to form an aromatic cyano compound of formula (IIb); and
(ⅱ) 화학식 Ⅱb의 화합물을 알칼리 알콕사이드, 알칼리 아록사이드, 알칼리 아릴알콕사이드 또는 알칼리 헤테로아릴알콕사이드와, 임의로는 구리를 포함하는 촉매의 존재하에 반응시켜 화학식 Ⅲ의 화합물을 생성하는 단계를 포함하는, 화학식 III의 화합물의 제조 방법을 제공한다.(Ii) reacting a compound of Formula IIb with an alkali alkoxide, alkali alkoxide, alkali arylalkoxide or alkali heteroarylalkoxide in the presence of a catalyst comprising optionally copper to produce a compound of Formula III Provided are methods of preparing the compounds of III.
; ;
상기식에서, In the above formula,
X는 각각 독립적으로 염소, 브롬 또는 요오드이며,Each X is independently chlorine, bromine or iodine,
R은 수소 원자, (C1-C6)알킬, 아릴, 아릴(C1-C2)알킬, 헤테로아릴 또는 헤테로아릴(C1-C2)알킬; 또는 (C1-C3)알킬 및 (C1-C3)알콕시로부터 독립적으로 선택된 1 내지 3개의 치환기로 치환된 (C1-C6)알킬, 아릴, 아릴(C1-C2)알킬,헤테로아릴 또는 헤테로아릴(C1-C2)알킬이고,R is a hydrogen atom, (C 1 -C 6 ) alkyl, aryl, aryl (C 1 -C 2 ) alkyl, heteroaryl or heteroaryl (C 1 -C 2 ) alkyl; Or (C 1 -C 3) alkyl and (C 1 -C 3) alkoxy substituted with one to three substituents independently selected from (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 2) alkyl, Heteroaryl or heteroaryl (C 1 -C 2 ) alkyl,
R1은 CHR2R3, 아릴, 아릴(C1-C2)알킬 또는 헤테로아릴(C1-C2)알킬; 또는 (C1-C3)알킬 및 (C1-C3)알콕시로부터 독립적으로 선택된 1 내지 3개의 치환기로 치횐된 아릴, 아릴(C1-C2)알킬 또는 헤테로아릴(C1-C2)알킬이고,R 1 is CHR 2 R 3 , aryl, aryl (C 1 -C 2 ) alkyl or heteroaryl (C 1 -C 2 ) alkyl; Or (C 1 -C 3) alkyl and (C 1 -C 3) an independently with one to three substituents selected from alkoxy chihoen aryl, aryl (C 1 -C 2) alkyl or heteroaryl (C 1 -C 2 Alkyl,
R2와 R3은 각각 독립적으로 수소 원자 또는 (C1-C5)알킬이거나 (C1-C2)알콕시로 치환된 (C1-C3)알킬이다.R 2 and R 3 are each independently a hydrogen atom or (C 1 -C 5) alkyl or (C 1 -C 2) alkoxy (C 1 -C 3) alkyl substituted with.
본 발명은 또한 강산이나 강염기를 사용하여 화학식 III의 화합물을 가수분해하여 화학식 Ⅳa의 화합물을 제조하는 방법을 제공하며, 필요한 경우, 추가로 화학식 IVa의 화합물을 에테르 분리 시약을 사용하여 화학식 V의 화합물로 전환시키는 방법을 포함한다.The present invention also provides a process for preparing a compound of formula IVa by hydrolysis of a compound of formula III using a strong acid or strong base, and, if necessary, further adding the compound of formula IV using an ether separation reagent. To convert to.
, ,
상기식에서, In the above formula,
R은 수소 원자, (C1-C6)알킬, 아릴, 아릴(C1-C2)알킬, 헤테로아릴 또는 헤테로아릴(C1-C2)알킬; 또는 (C1-C3)알킬 및 (C1-C3)알콕시로부터 독립적으로 선택된 1 내지 3개의 치환기로 치횐된 (C1-C6)알킬, 아릴, 아릴(C1-C2)알킬, 헤테로아릴 또는 헤테로아릴(C1-C2)알킬이고,R is a hydrogen atom, (C 1 -C 6 ) alkyl, aryl, aryl (C 1 -C 2 ) alkyl, heteroaryl or heteroaryl (C 1 -C 2 ) alkyl; Or (C 1 -C 3) alkyl and (C 1 -C 3) the chihoen alkoxy with 1 to 3 substituents independently selected from (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 2) alkyl, , Heteroaryl or heteroaryl (C 1 -C 2 ) alkyl,
R1은 CHR2R3, 아릴, 아릴(C1-C2)알킬 또는 헤테로아릴(C1-C2)알킬; 또는 (C1-C3)알킬 및 (C1-C3)알콕시로부터 독립적으로 선택된 1 내지 3개의 치환기로 치환된 아릴, 아릴(C1-C2)알킬 또는 헤테로아릴(C1-C2)알킬이고,R 1 is CHR 2 R 3 , aryl, aryl (C 1 -C 2 ) alkyl or heteroaryl (C 1 -C 2 ) alkyl; Or (C 1 -C 3) alkyl and (C 1 -C 3) alkoxy substituted with one to three substituents independently selected from aryl, aryl (C 1 -C 2) alkyl or heteroaryl (C 1 -C 2 Alkyl,
R2와 R3은 각각 독립적으로 수소 원자 또는 (C1-C5)알킬이거나 (C1-C2)알콕시로 치환된 (C1-C3)알킬이다.R 2 and R 3 are each independently a hydrogen atom or (C 1 -C 5) alkyl or (C 1 -C 2) alkoxy (C 1 -C 3) alkyl substituted with.
또한, 본 발명은 더 나아가 제1단계로 화학식 III의 화합물을 에테르 분리 시약과 반응시켜 화학식 Ⅳb의 화합물을 제조하는 방법을 제공하며, 필요한 경우, 제2단계로 화학식 Ⅳb의 화합물을 강산이나 강염기를 사용하여 화학식 Ⅴ의 화합물로 가수분해시키는 방법을 포함한다. The present invention further provides a method for preparing a compound of formula IVb by reacting a compound of formula III with an ether separation reagent in a first step, and, if necessary, converting the compound of formula IVb to a strong acid or strong base. To hydrolyze into compounds of formula V.
상기식에서,In the above formula,
R은 수소 원자, (C1-C6)알킬, 아릴, 아릴(C1-C2)알킬, 헤테로아릴 또는 헤테로아릴(C1-C2)알킬; 또는 (C1-C3)알킬 및 (C1-C3)알콕시로부터 독립적으로 선택된 1 내지 3개의 치환기로 치횐된 (C1-C6)알킬, 아릴, 아릴(C1-C2)알킬, 헤테로아릴 또는 헤테로아릴(C1-C2)알킬이고,R is a hydrogen atom, (C 1 -C 6 ) alkyl, aryl, aryl (C 1 -C 2 ) alkyl, heteroaryl or heteroaryl (C 1 -C 2 ) alkyl; Or (C 1 -C 3) alkyl and (C 1 -C 3) the chihoen alkoxy with 1 to 3 substituents independently selected from (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 2) alkyl, , Heteroaryl or heteroaryl (C 1 -C 2 ) alkyl,
R1은 CHR2R3, 아릴, 아릴(C1-C2)알킬 또는 헤테로아릴(C1-C2)알킬; 또는 (C1-C3)알킬 및 (C1-C3)알콕시로부터 독립적으로 선택된 1 내지 3개의 치환기로 치횐된 아릴, 아릴(C1-C2)알킬 또는 헤테로아릴(C1-C2)알킬이고,R 1 is CHR 2 R 3 , aryl, aryl (C 1 -C 2 ) alkyl or heteroaryl (C 1 -C 2 ) alkyl; Or (C 1 -C 3) alkyl and (C 1 -C 3) an independently with one to three substituents selected from alkoxy chihoen aryl, aryl (C 1 -C 2) alkyl or heteroaryl (C 1 -C 2 Alkyl,
R2와 R3은 각각 독립적으로 수소 원자 또는 (C1-C5)알킬이거나 (C1-C2)알콕시로 치환된 (C1-C3)알킬이다.R 2 and R 3 are each independently a hydrogen atom or (C 1 -C 5) alkyl or (C 1 -C 2) alkoxy (C 1 -C 3) alkyl substituted with.
상기 본 발명의 대체가능한 실시양태에서, 바람직한 방법은In such alternative embodiments of the invention, the preferred method is
각각의 X가 독립적으로 염소 또는 브롬이고,Each X is independently chlorine or bromine,
R이 수소 원자 또는 (C1-C6)알킬이고,R is a hydrogen atom or (C 1 -C 6 ) alkyl,
R1이 CHR2R3, 아릴, 아릴(C1-C2)알킬이고,R 1 is CHR 2 R 3 , aryl, aryl (C 1 -C 2 ) alkyl,
R2와 R3이 각각 독립적으로 수소 원자 또는 (C1-C2)알킬이거나 메톡시로 치환된 (C1-C2)알킬인 경우이다.The R 2 and R 3 each independently represent a case of substituted with a hydrogen atom or a (C 1 -C 2) alkyl or methoxy (C 1 -C 2) alkyl.
더욱 바람직한 방법은, 각각의 X가 염소이고, R이 수소 원자 또는 (C1-C3)알킬이고, R1이 CHR2R3이고 R2와 R3 이 각각 독립적으로 수소 원자 또는 (C1-C2)알킬인A more preferred method is that each X is chlorine, R is a hydrogen atom or (C 1 -C 3 ) alkyl, R 1 is CHR 2 R 3 and R 2 and R 3 are each independently a hydrogen atom or (C 1 -C 2 ) alkyl phosphorus
경우이다.If it is.
더욱 더 바람직한 방법은, R이 메틸 또는 에틸이고, R2가 수소 원자이고, R3이 수소 원자 또는 메틸인 경우이다.Even more preferred method is when R is methyl or ethyl, R 2 is a hydrogen atom, and R 3 is a hydrogen atom or methyl.
본 명세서에서 사용된, "알킬"이라는 용어는 직쇄 및 분지된 지방족 탄화수소 사슬을 의미하고, 예를 들어, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 2급-부틸, 3급-부틸, 이소아밀 및 n-헥실 등이다.As used herein, the term "alkyl" refers to a straight and branched aliphatic hydrocarbon chain, for example methyl, ethyl, n -propyl, isopropyl, n -butyl, secondary-butyl, tertiary- Butyl, isoamyl and n -hexyl and the like.
용어 "알콕시"는 산소 원자에 부착되어 있는 직쇄 및 분지된 지방족의 탄화수소 사슬을 의미하고, 예를 들어, 메톡시, 에톡시, n-프로폭시, 이소프로폭시 등이다,The term "alkoxy" means a straight and branched aliphatic hydrocarbon chain attached to an oxygen atom, for example methoxy, ethoxy, n -propoxy, isopropoxy, and the like.
용어 "아릴"은 방향족 환 계을 의미하고, 예를 들어 페닐, 1-나프틸, 2-나프틸 등이다,The term "aryl" means an aromatic ring system, for example phenyl, 1-naphthyl, 2-naphthyl and the like,
용어 "아릴알킬"은 알킬렌 그룹에 부착되어 있는 아릴 그룹을 의미하고, 예를 들어, 벤질, 펜에틸 등이다.The term "arylalkyl" refers to an aryl group attached to an alkylene group, for example benzyl, phenethyl and the like.
용어 "헤테로아릴"은 방향족의 헤테로사이클릭 그룹을 의미한다. 헤테로아릴알킬과 같이 다른 그룹의 헤테로아릴잔기 및 헤테로아릴환은 전형적으로, 벤젠 환과 같은 하나 이상의 다른 방향족, 헤테로방향족 또는 헤테로사이클릭 환에 융합될 수 있는 하나 이상의 산소, 질소, 또는 황 원자를 함유하는 5 또는 6원 방향족 환이다. 헤테로아릴 그룹의 예를 들면, 여기에 국한되는 것은 아니지만, 티에닐, 퓨릴, 피롤릴, 트리아졸릴, 티아졸릴, 옥사졸릴, 이속사졸릴, 티아졸릴, 이소티아졸릴, 피리딜, 피리미디닐, 피라지닐, 피리다지닐, 트리아지닐, 벤조퓨라닐, 벤조티에닐, 인돌릴, 퀴나졸리닐, 아크리디닐, 퓨리닐 및 퀴노살리닐 등이다.The term "heteroaryl" refers to an aromatic heterocyclic group. Heteroaryl residues and heteroaryl rings of other groups, such as heteroarylalkyl, typically contain one or more oxygen, nitrogen, or sulfur atoms that can be fused to one or more other aromatic, heteroaromatic, or heterocyclic rings, such as benzene rings. 5 or 6 membered aromatic ring. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, Pyrazinyl, pyridazinyl, triazinyl, benzofuranyl, benzothienyl, indolyl, quinazolinyl, acridinyl, purinyl and quinosalinyl and the like.
"헤테로아릴알킬"이라는 용어는 알킬렌 그룹이 부착되어 있는 헤테로아릴 그룹을 의미하고, 예를 들면 퍼퓨릴, 테닐, 니코티닐 등이다.The term "heteroarylalkyl" refers to a heteroaryl group to which an alkylene group is attached, for example perfuryl, tenyl, nicotinyl and the like.
"알칼리"라는 용어는 리듐, 칼륨 또는 나트륨 원자를 의미한다. The term "alkali" means a lithium, potassium or sodium atom.
화학식 I의 화합물을 화학식 Ⅱa의 화합물로 전화시키거나 또는 화학식 Ⅱb의 화합물을 화학식 III의 화합물로 전환시키는데 사용되는 모노알콕시화 반응 또는 모노아록시화 반응은 촉매가 존재하거나 존재하지 않는 상태에서 행할 수 있다, 촉매를 사용할 경우, 적합한 촉매로는 염화구리(I), 브롬화구리(I), 요오드화구리(I), 시안화구리(I), 염화구리(II), 산화구리(II), 황산구리(II) 및 원소 구리가 포함된다. 시안화구리(I)가 바람직한 촉매이다. 구리를 포함하는 촉매는 분말, 또는 운반체에 부착된 구리 등과 같이 여러 형태로서 존재할 수 있는데, 그 중에서도 분말의 형태가 특히 바람직하다, 촉매가 사용될 경우, 사용 비율은 화학식 I 또는 화학식 Ⅱb의 화합물을 기준으로 0.1 내지 100mol %가 된다. 바람직한 사용 비율은 0.5 내지 25mol %이다. 더 바람직한 사용 비율은 1 내지 10mol% 이다.The monoalkoxylation or monoaroxylation reaction used to convert a compound of formula (I) to a compound of formula (IIa) or to convert a compound of formula (IIb) to a compound of formula (III) can be carried out with or without a catalyst. When a catalyst is used, suitable catalysts include copper chloride (I), copper bromide (I), copper iodide (I), copper cyanide (I), copper chloride (II), copper oxide (II), copper sulfate (II) And elemental copper. Copper cyanide (I) is the preferred catalyst. The catalyst comprising copper may exist in various forms, such as powder or copper attached to a carrier, with the powder in particular being particularly preferred. When catalysts are used, the proportions used are based on compounds of formula (I) or formula (IIb). 0.1 to 100 mol%. Preferred proportions are 0.5 to 25 mol%. A more preferable use ratio is 1-10 mol%.
구리 촉매를 지지하는데 사용될 수 있는 적합한 운반체로는, 이에 국한되지는 않지만, 실리카, 탄소, 알루미나, 탄산칼슘 등을 포함하여 여러 가지가 있다.Suitable carriers that can be used to support the copper catalysts include, but are not limited to, silica, carbon, alumina, calcium carbonate, and the like.
화학식 I의 화합물을 화학식 IIa의 화합물로 전화시키거나 화학식 Ⅱb의 화합물을 화학식 III의 화합물로 전화시키는데 사용되는 적합한 알칼리 알콕사이드 시약으로는, 이에 국한되지는 않지만, 나트륨 메톡사이드, 칼륨 메톡사이드, 나트륨 에톡사이드 등을 예로 들 수 있다. 마찬가지로, 적합한 알칼리 아록사이드로는 나트륨 페녹사이드, 칼륨 페녹사이드 및 리튬 페녹사이드 등이 포함된다. 적합한 알칼리 아릴알콕사이드로는 나트륨 벤족사이드 등이 포함된다. 적합한 알칼리 헤테로아릴알콕사이드로는 칼륨 테녹사이드 등이 포함된다. 알칼리 알콕사이드, 알칼리 아록사이드, 알칼리 아릴알콕사이드 및 헤테로아릴알콕사이드는 통상, 할로겐으로 치환된 방향족 화합물을 기준으로 100 내지 200mol %의 양으로 사용한다. Suitable alkali alkoxide reagents used to convert a compound of Formula I to a compound of Formula IIa or to convert a compound of Formula IIb to a compound of Formula III include, but are not limited to, sodium methoxide, potassium methoxide, sodium ethoxy The side etc. are mentioned, for example. Likewise suitable alkali alkoxides include sodium phenoxide, potassium phenoxide and lithium phenoxide and the like. Suitable alkali arylalkoxides include sodium benzoside and the like. Suitable alkali heteroarylalkoxides include potassium tenoxide and the like. Alkali alkoxides, alkali alkoxides, alkali aryl alkoxides and heteroaryl alkoxides are usually used in amounts of 100 to 200 mol%, based on the aromatic compounds substituted with halogens.
본 발명의 방법에서는 화학식 I 화합물의 방향족 환의 단일 할로겐 그룹을 선택적으로 알콕시, 아록시, 아릴알콕시, 또는 헤테로아릴알콕시 그룹으로 대체할 수 있다. 한 예로서, 본 발명에서는 1-알킬-2,6-디할로벤젠을 1-알킬-6-(알콕시 또는 아록시 또는 아릴알콕시 또는 헤테로아릴알콕시)-2-할로벤젠으로, 80%이상의 선택율로서, 모노알콕시화, 모노아록시화, 모노아릴알콕시화 또는 모노헤테로아릴알콕시화 할 수 있다. 바람직한 조건을 사용하면, 선택율은 85% 이상이 된다. 더욱 바람직한 조건하에서는 선택율이 90%이상이 된다. 이 기술분야에서 숙련된 기술자들에게 알려진 바와 같이, 통상적으로 전환율이 보다 낮을 때 선택율은 더 높아진다. 예를 들어, 2,6-디클로로톨루엔이 메톡사이드와 반응할 경우, 6-클로로-2-메톡시톨루엔으로의 선택율은 70% 전화율일 때, 99%이상이다. 전환율이 93%로 증가하면, 선택율은 약 95%까지 감소하게 된다. In the process of the invention, a single halogen group of the aromatic ring of the compound of formula I can optionally be replaced with an alkoxy, aryl, arylalkoxy, or heteroarylalkoxy group. As an example, in the present invention, 1-alkyl-2,6-dihalobenzene is 1-alkyl-6- (alkoxy or aryl or arylalkoxy or heteroarylalkoxy) -2-halobenzene, with a selectivity of at least 80%. , Monoalkoxylation, monoaroxylation, monoarylalkoxylation or monoheteroarylalkoxylation can be carried out. If preferred conditions are used, the selectivity is 85% or more. Under more preferable conditions, the selectivity is 90% or more. As is known to those skilled in the art, the selectivity is typically higher when the conversion rate is lower. For example, when 2,6-dichlorotoluene reacts with methoxide, the selectivity to 6-chloro-2-methoxytoluene is at least 99% at 70% conversion. If the conversion rate increases to 93%, the selectivity decreases by about 95%.
단일 할로겐 그룹을 치환하는데 대한 반응속도는 적합한 용매 또는 용매의 혼합액을 사용할 경우 증가하게 된다. 디메틸 설폭사이드(DMSO), 디메틸포름아미드The reaction rate for substituting a single halogen group is increased when using a suitable solvent or mixture of solvents. Dimethyl Sulfoxide (DMSO), Dimethylformamide
(DMF), 1-메틸-2-피롤리디논(NMP), 디메틸설페이트, 에틸 아세테이트, 및 메탄올 과 에탄올과 같은 적합한 알코올류 등이 바람직한 용매이며, DMSO와 NMF가 더욱 바람직하다. 반응은 통상 65 내지 160℃에서 수행하며, 90℃ 이상이 바람직하다.(DMF), 1-methyl-2-pyrrolidinone (NMP), dimethylsulfate, ethyl acetate, and suitable alcohols such as methanol and ethanol are preferred solvents, and DMSO and NMF are more preferred. Reaction is normally performed at 65-160 degreeC, and 90 degreeC or more is preferable.
화학식 I의 화합물을 화학식 IIb의 화합물로 전환시키거나, 화학식 IIa의 화합물을 화학식 III의 화합물로 전환시키는데 이용되는 시안화 반응은 전형적으로 니켈을 포함하는 촉매의 존재하에서 수행한다. 이와 같은 촉매로는, 이에 국한되지는 않지만, 브롬화니켈(II), 아연 및 트리페닐포스핀의 혼합물, 디브로모비스(트리페닐포스핀)니켈, 아연 및 트리페닐포스핀의 혼합물, 디클로로비스(트리페닐포스핀)니켈, 아연 및 트리페닐포스핀의 혼합물 및 트리스(트리페닐포스핀)니켈 등이 있다. 이와 같은 상업용으로 시판되는 촉매들을 조합하여 사용할 수도 있다. 촉매는 할로겐으로 치환된 방향족 화합물의 양을 기준으로 보통 1 내지 10mol%의 양으로 사용한다.The cyanation reaction used to convert the compound of formula (I) to the compound of formula (IIb) or the compound of formula (IIa) to the compound of formula (III) is typically carried out in the presence of a catalyst comprising nickel. Such catalysts include, but are not limited to, nickel (II) bromide, mixtures of zinc and triphenylphosphine, dibromobis (triphenylphosphine) nickel, mixtures of zinc and triphenylphosphine, dichlorobis ( Triphenylphosphine) nickel, mixtures of zinc and triphenylphosphine and tris (triphenylphosphine) nickel and the like. Such commercially available catalysts may be used in combination. The catalyst is usually used in an amount of 1 to 10 mol% based on the amount of the aromatic compound substituted by halogen.
적합한 시안화 시약으로는, 이에 국한되지는 않지만, 시안화나트륨, 시안화칼륨, 시안화리튬, 아세톤 시아노하이드린과 같은 시아노히드린류, 시안화구리(I) 등이 포함된다. 전형적으로 시안화 시약은, 할로겐으로 치환된 방향족 화합물을 기준으로 100 내지 200%mol 당량의 양으로 사용한다. Suitable cyanide reagents include, but are not limited to, sodium cyanide, potassium cyanide, lithium cyanide, cyanohydrins such as acetone cyanohydrin, copper cyanide, and the like. Typically cyanation reagents are used in amounts of 100 to 200% molar equivalents based on the aromatic compounds substituted by halogen.
적합한 용매를 종종 시안화 반응에 사용한다. 메탄올 및 에탄올과 같은 알코올, 테트라하이드로퓨란(THF), 헥사메틸포스포르아미드(HMPA), 아세토니트릴(ACN), 1-메틸-2-피롤리디논(NMP), 톨루엔 및 기타 방향족 용매를 사용할 수 있다. 적합한 용매의 혼합물도 역시 사용할 수 있다. 바람직한 용매로는 THF, NMP 및 ACN이다. 시안화 반응은 20 내지 200℃에서 수행하며, 바람직하게는 30 내지 180℃, 보다 바람직하게는 40 내지 140℃에서 수행한다. 시안화 반응의 수율은 일반적으로 50%이상이다. 바람직한 조건을 사용할 경우, 75% 이상의 수율을 수득한다. 더욱 바람직한 조건을 사용하면, 출발 물질의 중량을 기준으로 90%이상의 수율을 얻게 된다.Suitable solvents are often used in cyanation reactions. Alcohols such as methanol and ethanol, tetrahydrofuran (THF), hexamethylphosphoramide (HMPA), acetonitrile (ACN), 1-methyl-2-pyrrolidinone (NMP), toluene and other aromatic solvents can be used. have. Mixtures of suitable solvents may also be used. Preferred solvents are THF, NMP and ACN. The cyanation reaction is carried out at 20 to 200 ° C, preferably at 30 to 180 ° C, more preferably at 40 to 140 ° C. The yield of cyanation reaction is generally at least 50%. When preferred conditions are used, yields of at least 75% are obtained. Using more preferred conditions, a yield of at least 90% is obtained, based on the weight of the starting material.
이 기술 분야에서 숙련된 기술자들에게 알려진 조건을 사용하여, 화학식 III의 방향족 시아노 화합물을 화학식 IVa의 산으로 가수분해하거나 또는 화학식 IVb의 방향족 시아노 화합물을 화학식 V의 산으로 가수분해시킬 수 있다. 반응은 통상 강산 또는 강염기의 존재하에 수행한다. 적합한 산으로는 염산, 황산 및 인산과 같은 강한 무기산을 포함하며, 황산이 바람직하다. 적합한 염기로는 수산화 나트륨, 수산화 칼륨이 포함된다. 가수분해 반응은 주위 온도 내지 180℃의 온도에서 수행할 수 있다.Conditions known to those skilled in the art can be used to hydrolyze the aromatic cyano compound of Formula III to an acid of Formula IVa or to hydrolyze the aromatic cyano compound of Formula IVb to an acid of Formula V. . The reaction is usually carried out in the presence of a strong acid or strong base. Suitable acids include strong inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, with sulfuric acid being preferred. Suitable bases include sodium hydroxide, potassium hydroxide. The hydrolysis reaction can be carried out at ambient temperature to a temperature of 180 ° C.
에테르 분리반응은 이 기술 분야에서 숙련된 기술자들에게 알려진 반응을 사용하여 수행할 수 있다. 예를 들어, 이 반응은 화학식 III의 화합물을, 염산, 브롬화수소산 또는 요오드화수소산 등과 같은 브뢴스테드 산, 삼플루오로화 붕소 에테레이트와 같은 루이스산, 나트륨 메톡사이드, 피리딘 또는 메틸아민과 같은 염기, 또는 피리딘 하이드로클로라이드와 같은 강산-약염기 염 등과 함께Ether separation reactions can be carried out using reactions known to those skilled in the art. For example, this reaction may be carried out by a compound of formula III, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, or the like, a Lewis acid such as boron trifluoride etherate, a base such as sodium methoxide, pyridine or methylamine. Or strong acid-weak base salts such as pyridine hydrochloride, etc.
가열하여, 하이드록시로 치환된 화학식 IVb의 화합물을 형성한다. 적합한 반응 온도는 주위 온도 내지 200℃이상이다. 비슷한 방법으로, 화학식 IVa의 화합물을 화학식 V로 전환시킬 수 있다.Heating forms a compound of formula IVb substituted with hydroxy. Suitable reaction temperatures are from ambient temperature up to 200 ° C. In a similar manner, compounds of formula IVa can be converted to formula V.
다음의 실시예 및 실험방법들은 실무자에게 지침으로 제공되는 것이며, 특허청구범위에 의해 한정된 발명의 범위를 제한하려는 것은 아니다.The following examples and experimental methods are provided as a guide to the practitioner and are not intended to limit the scope of the invention as defined by the claims.
실시예 1: 2,6-디클로로톨루엔(DCT)의 6-클로로-2-메톡시톨루엔(MCT)으로의 메톡시화 Example 1 Methoxylation of 2,6-Dichlorotoluene (DCT) to 6-chloro-2-methoxytoluene (MCT)
온도 조절기, 응축기, 자기 교반기가 장착되어 있는 500mL 플라스크에, DCT(0.31mol) 50g, 95% 칼륨 메톡사이드(0.41mol) 30g 및 1-메틸-2-피롤리디논(NMP) 25g을 장입하였다. 혼합물을 100℃에서 2시간 동안 교반한 다음, 120℃에서 18시간 동안 교반하였다. 그 다음으로 디메틸 설페이트(10g, 0.08mol)를 첨가한 후, 생성된 혼합물을 120℃에서 5시간 동안 더 교반하였다. 이 이후에, 혼합물을 주위 온도까지 냉각하고 여과하였다. 여과 케이크를 이소프로판올(3 x 65mL)로 세척하였다. 혼합된 여액과 세척액을 분석한 결과 MCT 40g이 생성된 것으로 나타났다. 수율: 82%. In a 500 mL flask equipped with a temperature controller, a condenser, and a magnetic stirrer, 50 g of DCT (0.31 mol), 30 g of 95% potassium methoxide (0.41 mol) and 25 g of 1-methyl-2-pyrrolidinone (NMP) were charged. The mixture was stirred at 100 ° C. for 2 hours and then at 120 ° C. for 18 hours. Then dimethyl sulfate (10 g, 0.08 mol) was added and the resulting mixture was further stirred at 120 ° C. for 5 hours. After this time, the mixture was cooled to ambient temperature and filtered. The filter cake was washed with isopropanol (3 x 65 mL). Analysis of the mixed filtrate and wash solution showed that 40 g of MCT were produced. Yield 82%.
실시예 2: DMF 중에서 CuCN을 사용한 DCT의 메톡시화 Example 2 Methoxylation of DCT with CuCN in DMF
온도 조절기, 응축기 및 자기 교반기가 장착된 25mL 플라스크에 DCT(12.4mmol) 2.00g, NaOCH3(24.1mol) 1.30g, CuCN(1.2mmol) 0.10g 및 DMF 10.0g을 장입하였다. 혼합물을 120℃로 가열한후 질소하에 교반하였다. 가스 크로마토그래피(GC) 분석 결과, 17시간 후에 MCT의 수율은 88.6%였고, 10.0%의 DCT가 남았다. 19시간 후에 MCT의 수율은 92.8%로 증가하였고, 이 때 1.4%의 DCT가 아직 반응하지 않은 상태였다.To a 25 mL flask equipped with a thermostat, condenser and magnetic stirrer was charged 2.00 g DCT (12.4 mmol), 1.30 g NaOCH 3 (24.1 mol), 0.10 g CuCN (1.2 mmol) and 10.0 g DMF. The mixture was heated to 120 ° C. and stirred under nitrogen. Gas Chromatography (GC) analysis showed that the yield of MCT was 88.6% after 17 hours, leaving 10.0% of DCT. After 19 hours, the yield of MCTs increased to 92.8%, at which point 1.4% of DCT had not yet responded.
실시예 3: DMF 중에서 CuCN을 사용한 DCT의 메톡시화 Example 3 Methoxylation of DCT with CuCN in DMF
온도 조절기, 응축기 및 자기 교반기가 장착된 25mL 플라스크에 DCT(31.0mmol) 5.00g, NaOCH3(37.0mmol) 2.00g, CuCN(1.7mmol) 0.15g 및 DMF 5.00g을 장입하였다. 혼합물을 150℃로 가열한후 질소하에 교반하였다. 가스 크로마토그래피(GC) 분석 결과, 17시간 후에 MCT의 수율은 64.8%였고, 28.1%의 DCT가 남아있었다. 26시간 후에 MCT의 수율은 76.0%로 증가하였고,이 때 16.3%의 DCT가 아직 반응하지 않은 상태였다.In a 25 mL flask equipped with a thermostat, condenser and magnetic stirrer was charged 5.00 g of DCT (31.0 mmol), 2.00 g of NaOCH 3 (37.0 mmol), 0.15 g of CuCN (1.7 mmol) and 5.00 g of DMF. The mixture was heated to 150 ° C. and stirred under nitrogen. Gas chromatography (GC) analysis showed that after 17 hours the yield of MCT was 64.8% and 28.1% of DCT remained. After 26 hours, the yield of MCT increased to 76.0%, at which time 16.3% of DCT had not yet responded.
실시예 4: DMSO 중의 CuCN을 사용한 DCT의 메톡시화 Example 4 Methoxylation of DCT with CuCN in DMSO
온도 조절기, 응축기 및 자기 교반기가 장착된 25mL 플라스크에 DCT(31.0mmol) 5.00g, NaOCH3(37.0mmol) 2.00g, CuCN(1.7mmol) 0.15g 및 DMSO 5.0g을 장입하였다. 혼합물을 140℃로 가열한후 질소하에 교반하였다. 가스 크로마토그래피(GC) 분석 결과, 6시간 후에 MCT의 수율은 82.8%였고, 12.4%의 DCT가 남아있었다. 12시간 후에 MCT의 수율은 86.1%로 증가하였고, 이 때 7.2%의 DCT가 아직 반응하지 않은 상태였다. In a 25 mL flask equipped with a thermostat, condenser and magnetic stirrer was charged 5.00 g DCT (31.0 mmol), 2.00 g NaOCH 3 (37.0 mmol), 0.15 g CuCN (1.7 mmol) and 5.0 g DMSO. The mixture was heated to 140 ° C. and stirred under nitrogen. Gas chromatography (GC) analysis showed that after 6 hours the yield of MCT was 82.8% and 12.4% of DCT remained. After 12 hours, the yield of MCTs increased to 86.1% at which time 7.2% of DCT had not yet responded.
실시예 5: 메탄올중의 CuBr을 사용한 DCT의 메톡시화 Example 5 Methoxylation of DCT with CuBr in Methanol
온도계, 응축기 및 자기 교반기가 장착된 25mL 플라스크에 DCT(12.4mmol) 2.00g, 25% NaOCH3 용액(메탄올 용매, 23.1mmol) 5.00g, CuBr(1.7mmol) 0.25g 및 에틸 아세테이트 0.44g을 장입하였다. 혼합물을 가열하여 환류하고 질소하에 교반하였다. 가스 크로마토그래피(GC) 분석 결과, 5시간 후에 MCT 의 수율은 7.3%였고, 92.1%의 DCT가 남아있었다. 24시간 후에 MCT의 수율은 25.2%로 증가하였고, 이 때 65.2%의 DCT가 아직 반응하지 않은 상태였다.A 25 mL flask equipped with a thermometer, condenser and magnetic stirrer was charged with 2.00 g of DCT (12.4 mmol), 5.00 g of 25% NaOCH 3 solution (methanol solvent, 23.1 mmol), 0.25 g of CuBr (1.7 mmol) and 0.44 g of ethyl acetate. . The mixture was heated to reflux and stirred under nitrogen. Gas chromatography (GC) analysis showed that after 5 hours the yield of MCT was 7.3% and 92.1% of DCT remained. After 24 hours, the yield of MCTs increased to 25.2%, at which time 65.2% of DCT had not yet responded.
실시예 6: MCT를 2-시아노-6-메톡시톨루엔으로 전화하기 위한 시안화 반응 Example 6 Cyanation Reaction to Convert MCT to 2-Cyano-6-methoxytoluene
환류 응축기, 자기 교반기 및 온도 조절기가 장착된 50mL 3-구 플라스크에 브롬화 니켈(II)(0.22g, 1.0mmol), 아연 분말(0.20g, 3.0mmol), 트리페닐포스핀(1.31g, 5.0mmol) 및 테트라하이드로퓨란 15mL를 첨가하였다. 혼합물을 50℃까지 가열하고 질소하에 30분간 교반하였다. 이 단계 후, 6-클로로-2-메톡시톨루엔(4.70g, 30.0mmol)을 첨가한 다음, 온도를 60℃로 상승시켰다. 그 다음, 혼합물을 30분간 더 교반하였다. 이어서, 시안화 칼륨(2.65g, 40.7mmol)을 5시간 이상에 걸쳐, 똑같이 10 부분의 분량으로 나누어 점진적으로 첨가하였다. 첨가 완료 시점에서, 혼합물을 60℃에서 18시간 동안 교반하였다. 가스 크로마토그래피(GC) 분석 결과, 이 기간의 종료 시점에서 반응 혼합물의 조성은 2-시아노-6-메톡시톨루엔 71.5%, 6-클로로-2-메톡시톨루엔 22.8%, 2-메톡시톨루엔 4.1% 및 2,2'-디메틸-3,3'-디메톡시비페닐 0.5%인 것으로 나타났다. 소비된 출발 물질을 기준으로 시안화 반응의 수율은 92.6%였다.50 mL three-necked flask equipped with reflux condenser, magnetic stirrer and thermostat in nickel (II) bromide (0.22 g, 1.0 mmol), zinc powder (0.20 g, 3.0 mmol), triphenylphosphine (1.31 g, 5.0 mmol ) And 15 mL of tetrahydrofuran were added. The mixture was heated to 50 ° C. and stirred for 30 minutes under nitrogen. After this step, 6-chloro-2-methoxytoluene (4.70 g, 30.0 mmol) was added and then the temperature was raised to 60 ° C. Then, the mixture was further stirred for 30 minutes. Potassium cyanide (2.65 g, 40.7 mmol) was then added gradually over a period of 5 hours or more, divided into 10 portions. At the end of the addition, the mixture was stirred at 60 ° C. for 18 hours. As a result of gas chromatography (GC) analysis, the composition of the reaction mixture at the end of this period was 71.5% 2-cyano-6-methoxytoluene, 22.8% 6-chloro-2-methoxytoluene, 2-methoxytoluene 4.1% and 2,2'-dimethyl-3,3'-dimethoxybiphenyl was found to be 0.5%. The yield of cyanation reaction was 92.6% based on the starting material consumed.
실시예 7: 6-클로로-2-메톡시톨루엔(MCT)의 2-시아노-6-메톡시톨루엔(CMT)으로의 시안화 Example 7 Cyanation of 6-chloro-2-methoxytoluene (MCT) to 2-cyano-6-methoxytoluene (CMT)
공정 1(CCW09-18):Process 1 (CCW09-18):
환류 응축기, 자기 교반기 및 온도 조절기가 장착된 50mL 3-구 플라스크에 디브로모비스(트리페닐포스핀)니켈(1.00g, 1.34mmol), 아연 분말(0.25g, 3.82mmol), 트리페닐포스핀(1.50g, 5.72mmol), 6-클로로-2-메톡시톨루엔(MCT, 10.0g, 63.8g), 1-메틸-2-피롤리디논(NMP) 15.0g 및 아세토니트릴 7.5g을 첨가하였다. 플라스크를 질소로 5분간 세정하였다. 혼합물을 60℃로 가열한 다음, 질소하에 30분간 가열하였다. 이 단계 후, 온도를 70℃로 상승시킨 다음, 시안화칼륨(8.5g, 130mmol, 분말 상태)을 조금씩 4시간에 걸쳐 첨가하였다. 첨가 완료 시점에서, 생성된 혼합물을 70℃에서 18시간 동안 교반하였다. 가스 크로마토그래피(GC) 분석 결과, 이 기간의 종료 시점에서 반응 혼합물의 조성(FID에 의한 영역%)은 다음과 같았다: 2-시아노톨루엔(CT) 3.45%, MCT 5.91%, 2-시아노-6-메톡시톨루엔(CMT) 90.30%.Dibromobis (triphenylphosphine) nickel (1.00 g, 1.34 mmol), zinc powder (0.25 g, 3.82 mmol), triphenylphosphine (50 mL 3-necked flask equipped with reflux condenser, magnetic stirrer and temperature controller) 1.50 g, 5.72 mmol), 6-chloro-2-methoxytoluene (MCT, 10.0 g, 63.8 g), 15.0 g 1-methyl-2-pyrrolidinone (NMP) and 7.5 g acetonitrile were added. The flask was washed with nitrogen for 5 minutes. The mixture was heated to 60 ° C. and then under nitrogen for 30 minutes. After this step, the temperature was raised to 70 ° C., and potassium cyanide (8.5 g, 130 mmol, powder) was added in portions over 4 hours. At the end of the addition, the resulting mixture was stirred at 70 ° C. for 18 hours. As a result of gas chromatography (GC) analysis, at the end of this period the composition of the reaction mixture (area% by FID) was as follows: 2.45% cyanotoluene (CT), 5.91% MCT, 2-cyano -6-methoxytoluene (CMT) 90.30%.
또한 진행되는 동안 GC 분석(DB-1 칼럼)을 사용하여 모니터하였다. 하기 표와 그래프는 GC 데이터로부터의 결과이다.It was also monitored using GC analysis (DB-1 column) during the run. The following table and graphs are the results from the GC data.
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공정 2(CCW09-50) :Process 2 (CCW09-50):
환류 응축기, 자기 교반기 및 온도 조절기가 장착된 50ml 3-구 플라스크에 디브로모비스(트리페닐포스핀)니켈(1.00g, 1.34mmol), 아연 분말(0.30g, 4.59mmol), 트리페닐포스핀(1.50g, 5.72mmol) 및 아세토니트릴 7.5g을 첨가하였다. 플라스크를 질소로 5분간 세정하였다. 이어서 혼합물을 60℃로 가열하고 질소하에 30분간 교반하였다. 이 단계 후 MCT(63.8mmol) 10g과 NMP(63.5mmol) 6.3g를 함유하는 MCT-NMP 혼합물을 첨가하고, 그 혼합물을 추가로 15분간 교반하였다. 이어서, 시안화칼륨(8.5g, 130mmol, 분말 상태)을 조금씩 4시간 걸쳐 첨가하였다. 첨가 완료 시점에서, 온도를 70℃로 상승시키고, 생성된 혼합물을 추가로 16시간 동안 교반하였다. GC 분석 결과(HP-35, 15m 칼럼), 이 기간의 종료 시점에서 혼합물의 조성(FID에 의한 영역%)은 다음과 같았다: CT 1.28%, MCT 3.37%, CMT 92.60%, 2,6-디메톡시톨루엔(DMT) 2.13%. Dibromobis (triphenylphosphine) nickel (1.00 g, 1.34 mmol), zinc powder (0.30 g, 4.59 mmol), triphenylphosphine (50 ml three-necked flask equipped with reflux condenser, magnetic stirrer and temperature controller) 1.50 g, 5.72 mmol) and 7.5 g acetonitrile were added. The flask was washed with nitrogen for 5 minutes. The mixture was then heated to 60 ° C. and stirred for 30 minutes under nitrogen. After this step, an MCT-NMP mixture containing 10 g of MCT (63.8 mmol) and 6.3 g of NMP (63.5 mmol) was added and the mixture was stirred for an additional 15 minutes. Potassium cyanide (8.5 g, 130 mmol, powder) was then added little by little over 4 hours. At the end of the addition, the temperature was raised to 70 ° C. and the resulting mixture was stirred for a further 16 hours. As a result of GC analysis (HP-35, 15 m column), at the end of this period the composition of the mixture (area% by FID) was as follows: CT 1.28%, MCT 3.37%, CMT 92.60%, 2,6-dime Oxytoluene (DMT) 2.13%.
또한 진행되는 동안 GC 분석(DB-1 칼럼)을 사용하여 반응을 모니터하였다. 하기 표와 그래프는 GC 데이터부터의 결과이다.The reaction was also monitored using GC analysis (DB-1 column) during the run. Tables and graphs below are from GC data.
공정 3(CCW09-52):Process 3 (CCW09-52):
환류 응축기, 자기 교반기 및 온도 조절기가 장착된 50mL 3-구 플라스크에 디브로모비스(트리페닐포스핀)니켈(1.00g, 1.34mmol), 아연 분말(0.30g, 4.59mmol), 트리페닐포스핀(1.50g, 5.72mmol) 및 아세토니트릴 7.5g을 첨가하였다. 플라스크를 질소로 5분간 세정하였다. 이어서 혼합물을 60℃로 가열하고 질소하에 30분간 교반하였다. 이 단계 후 MCT(63.8mmol) 10g 및 NMP(73.6mmol) 7.3g을 함유하는 MCT-NMP 혼합물을 첨가하고, 그 혼합물을 추가로 15분간 교반하였다. 이어서, 온도를 70℃로 상승시키고, 시안화칼륨(8.5g, 130mmol, 분말 상태)을 조금씩 4시간 에 걸쳐 첨가하였다. 첨가 완료 시점에서, 온도를 70℃로 상승시키고, 생성된 혼합물을 추가로 24시간 동안 교반하였다. GC 분석 결과, 이 단계의 종료 시점에서 혼합물의 조성(FID에 의한 영역%)은 다음과 같았다: CT 1.28%, MCT 3.37%, CMT 92.60%, 2,6-디메톡시톨루엔(DMT) 2.13%.Dibromobis (triphenylphosphine) nickel (1.00 g, 1.34 mmol), zinc powder (0.30 g, 4.59 mmol), triphenylphosphine (50 mL three-necked flask with reflux condenser, magnetic stirrer and temperature controller) 1.50 g, 5.72 mmol) and 7.5 g acetonitrile were added. The flask was washed with nitrogen for 5 minutes. The mixture was then heated to 60 ° C. and stirred for 30 minutes under nitrogen. After this step, an MCT-NMP mixture containing 10 g of MCT (63.8 mmol) and 7.3 g of NMP (73.6 mmol) was added and the mixture was stirred for an additional 15 minutes. The temperature was then raised to 70 ° C. and potassium cyanide (8.5 g, 130 mmol, powder) was added little by little over 4 hours. At the end of the addition, the temperature was raised to 70 ° C. and the resulting mixture was stirred for a further 24 hours. As a result of GC analysis, the composition of the mixture (% area by FID) at the end of this step was as follows: CT 1.28%, MCT 3.37%, CMT 92.60%, 2,6-dimethoxytoluene (DMT) 2.13%.
또한 진행되는 동안 GC 분석(DB-1 칼럼)을 사용하여 반응을 모니터하였다. 하기 표와 그래프는 GC 데이터로부터의 결과이다.The reaction was also monitored using GC analysis (DB-1 column) during the run. The following table and graphs are the results from the GC data.
실시예 8: 2-시아노-6-메톡시톨루엔(CMT)의 3-메톡시-2-메틸벤조산(MMBA)으로의 가수분해 Example 8 Hydrolysis of 2-cyano-6-methoxytoluene (CMT) to 3-methoxy-2-methylbenzoic acid (MMBA)
온도 조절기, 응축기 및 자기 교반기가 장착된 3-구 25mL 플라스크에 2-시아노-6-메톡시톨루엔(8.2mmol) 1.2g, 45% 수산화 칼륨 수용액(16.1mmol) 2.0g 및 에틸렌 글리콜 15g을 장입하였다. 혼합물을 가열하여 환류시키고 5시간 동안 교반하였다. 생성된 혼합물을 주위 온도까지 냉각하고, 물 30mL로 희석한 다음, 염화메틸렌(2 x 20mL)로 추출하였다. 수성층은 37% 염산을 사용하여 pH 2 이하로 될 때까지 산성화한 다음, 염화메틸렌(2 x 30mL)으로 추출하였다. 염화메틸렌 추출물은 혼합되었다. 염화메틸렌을 제거한 후, MMBA 1.2g을 수득하였다. 수율 : 89%.To a 3-neck 25 mL flask equipped with a thermostat, condenser and magnetic stirrer, charge 1.2 g 2-cyano-6-methoxytoluene (8.2 mmol), 2.0 g 45% aqueous potassium hydroxide solution (16.1 mmol) and 15 g ethylene glycol It was. The mixture was heated to reflux and stirred for 5 hours. The resulting mixture was cooled to ambient temperature, diluted with 30 mL of water and then extracted with methylene chloride (2 x 20 mL). The aqueous layer was acidified with 37% hydrochloric acid until pH 2 or less and then extracted with methylene chloride (2 x 30 mL). Methylene chloride extracts were mixed. After removal of methylene chloride, 1.2 g of MMBA was obtained. Yield 89%.
실시예 9: 3-메톡시-2-메틸벤조산의 3-하이드록시-2-메틸벤조산으로의 전환 공정 Example 9 Conversion of 3-methoxy-2-methylbenzoic acid to 3-hydroxy-2-methylbenzoic acid
20mL 압력 튜브에 3-메톡시-2-메틸벤조산(3.0mmol) 0.50g 및 48% 브롬화수소산(9.0mmol, 3.0eq.)1.52g을 장입하였다. 튜브를 봉한 다음, 오일욕에서 170℃로 가열하였다. 혼합물은 자기 교반기를 사용하여 4시간 동안 교반하였다. 이어서, 주위 온도까지 냉각하였다. 물질 일부분을 떼내어 진공하에 건조시켜 휘발성 성분을 제거하였다. 잔류물을 GC 및 NMR로 분석한 결과 순수한 3-하이드록시-2-메틸벤조산이 수득된 것으로 나타났다.In a 20 mL pressure tube was charged 0.50 g of 3-methoxy-2-methylbenzoic acid (3.0 mmol) and 1.52 g of 48% hydrobromic acid (9.0 mmol, 3.0 eq.). The tube was sealed and then heated to 170 ° C. in an oil bath. The mixture was stirred for 4 hours using a magnetic stirrer. Then cooled to ambient temperature. A portion of the material was removed and dried under vacuum to remove volatile components. Analysis of the residue by GC and NMR showed pure 3-hydroxy-2-methylbenzoic acid.
실시예 10: 2-시아노-6-메톡시톨루엔의 2-시아노-6-하이드록시톨루엔으로의 전환 공정 Example 10 Conversion of 2-cyano-6-methoxytoluene to 2-cyano-6-hydroxytoluene
20mL 압력 튜브에 2-시아노-6메톡시톨루엔(3.4mmol) 0.50g과 48% 브롬화수소산(10.2mmol, 3.0eq.) 1.73g을 장입하였다. 튜브를 봉한 다음, 오일욕에서 170℃로 가열하였다. 혼합물을 자기 교반기를 사용하여 4시간 동안 교반하였다. 이어서, 주위 온도까지 냉각시켰다. 물질 일부분을 떼내어 진공하에 건조시켜 휘발성 성분을 제거하였다. 잔류물을 GC 및 NMR로 분석한 결과 순수한 2-시아노-6-하이드록시톨루엔이 수득된 것으로 나타났다.Into a 20 mL pressure tube was charged 0.50 g of 2-cyano-6methoxytoluene (3.4 mmol) and 1.73 g of 48% hydrobromic acid (10.2 mmol, 3.0 eq.). The tube was sealed and then heated to 170 ° C. in an oil bath. The mixture was stirred for 4 hours using a magnetic stirrer. Then cooled to ambient temperature. A portion of the material was removed and dried under vacuum to remove volatile components. Analysis of the residue by GC and NMR showed pure 2-cyano-6-hydroxytoluene.
특허청구범위에서 한정된 본 발명의 취지 및 범주를 벗어남이 없이 본 발명을 변화시키거나 변형시킬 수 있다It is possible to change or modify the present invention without departing from the spirit and scope of the invention as defined in the claims.
상기한 바와 같이 본 발명의 방법에 의하면, 목적하는 벤조산 및 벤조니트릴을 보다 낮은 단가로 보다 높은 순도로 제조할 수 있다.As described above, according to the method of the present invention, the desired benzoic acid and benzonitrile can be produced with higher purity at lower cost.
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US08/884193 | 1997-07-01 | ||
US08/884,193 US5917079A (en) | 1996-09-24 | 1997-07-01 | Process for synthesizing benzoic acids |
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US6124500A (en) * | 1998-03-09 | 2000-09-26 | Rohm And Haas Company | Process for synthesizing benzoic acids |
IL133121A (en) * | 1998-12-08 | 2004-06-20 | Dow Agrosciences Llc | Process for making 2-alkyl-3-hydroxybenzoic acids |
US6331628B1 (en) | 1999-03-29 | 2001-12-18 | Nissan Chemical Industries, Ltd. | Process for the preparation of benzonitrile compounds |
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CN100386309C (en) * | 2006-06-09 | 2008-05-07 | 武汉大学 | Method for preparing 2- chlor-6- dialkoxy benzene nitrile |
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